title: Increased availability of angiotensin AT 1 receptors leads to sustained arterial constriction to angiotensin II in diabetes - role for Rho-kinase activation.
abstract: OBJECTIVE
  Antagonists of angiotensin AT(1) receptors elicit beneficial vascular effects in diabetes mellitus. We hypothesized that diabetes induces sustained availability of AT(1) receptors, causing enhanced arterial constriction to angiotensin II.
  
  
  METHODS
  To assess functional availability of AT(1) receptors, constrictions to successive applications of angiotensin II were measured in isolated skeletal muscle resistance arteries (∼150 µm) of Zucker diabetic fatty (ZDF) rats and of their controls (+/Fa), exposed acutely to high glucose concentrations (HG, 25 mM, 1 h). AT(1) receptors on cell membrane surface were measured by immunofluorescence.
  
  
  RESULTS
  Angiotensin II-induced constrictions to first applications were greater in arteries of ZDF rats (maximum: 82 ± 3% original diameter) than in those from +/Fa rats (61 ± 5%). Constrictions to repeated angiotensin II administration were decreased in +/Fa arteries (20 ± 6%), but were maintained in ZDF arteries (67 ± 4%) and in +/Fa arteries vessels exposed to HG (65 ± 6%). In ZDF arteries and in HG-exposed +/Fa arteries, Rho-kinase activities were enhanced. The Rho-kinase inhibitor, Y27632 inhibited sustained constrictions to angiotensin II in ZDF arteries and in +/Fa arteries exposed to HG. Levels of surface AT(1) receptors on cultured vascular smooth muscle cells (VSMCs) were decreased by angiotensin II but were maintained in VSMCs exposed to HG. In VSMCs exposed to HG and treated with Y27632, angiotensin II decreased surface AT(1) receptors.
  
  
  CONCLUSIONS
  In diabetes, elevated glucose concentrations activate Rho-kinase which inhibits internalization or facilitates recycling of AT(1) receptors, leading to increased functional availability of AT(1) receptors and sustained angiotensin II-induced arterial constriction.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, NY, USA. zsolt.bagi@pharm.ox.ac.uk
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.forename: Attila
authors.initials: A
authors.lastname: Feher
authors.forename: James
authors.initials: J
authors.lastname: Cassuto
authors.forename: Komala
authors.initials: K
authors.lastname: Akula
authors.forename: Nazar
authors.initials: N
authors.lastname: Labinskyy
authors.forename: Gabor
authors.initials: G
authors.lastname: Kaley
authors.forename: Akos
authors.initials: A
authors.lastname: Koller
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D054460:rho-Associated Kinases